Implantable Drug Delivery Device and Methods of Treating Male Genitourinary and Surrounding Tissues

ABSTRACT

A method is provided for local controlled delivery of a drug to the seminal vesicle, the prostate, the ejaculatory duct, or the vas deferens of a patient in need of treatment. In one embodiment, the method includes implanting a resorbable drug delivery device within the seminal vesicle, the prostate, the ejaculatory duct, or the vas deferens of the patient. The drug delivery device may include an elastic device body housing at least one drug reservoir which contains at least one drug. In a preferred embodiment, the method further includes releasing the drug from the device in a controlled manner to, typically directly to, the seminal vesicle, the prostate, the ejaculatory duct, or the vas deferens.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation-in-part of U.S. application Ser. No.11/463,956, filed Aug. 11, 2006, which claims benefit of U.S.Provisional Application No. 60/726,490, filed Oct. 12, 2005, and U.S.Provisional Application No. 60/707,676, filed Aug. 11, 2005, each ofwhich is incorporated herein by reference. This application also claimsbenefit of U.S. Provisional Application No. 61/087,687, filed Aug. 9,2008, which is incorporated herein by reference.

BACKGROUND OF THE INVENTION

This invention is generally in the field of medical devices, and moreparticularly relates to implantable drug delivery devices for controlledrelease of drug locally to a tissue site.

The efficacy of many drugs is directly related to the way in which theyare administered. Various systemic methods of drug delivery includeoral, intravenous, intramuscular, and transdermal. These systemicmethods may produce undesirable side effects and may result in themetabolization of the drug by physiological processes, ultimatelyreducing the quantity of drug to reach the desired site. Accordingly, avariety of devices and methods have been proposed to deliver drug in amore targeted manner, such as locally, to address many of the problemsassociated with systemic drug delivery.

Prostatitis is an inflammatory condition of the prostate gland.Typically, prostatitis is a painful disorder that presents with symptomsthat often include chronic pelvic pain, urinary dysfunction (in the formof frequency, urgency or weak stream, pain on urination) and sexualdysfunction. The condition is estimated to be prevalent among 10% of allmen and is believed to be symptomatic in half the male population atsome point in their lifetime. Prostatitis can occur either as an acuteinfection of the prostate gland, known as acute bacterial prostatitis,or more commonly as a recurring condition, known as chronic prostatitis.

Chronic prostatitis is characterized as being bacterial (CBP) orabacterial (ACP) based on the isolation of a suspected causativepathogen from the prostatic fluid or urine. Bacteria are believed tocause a significant percentage of chronic prostatitis cases, such as 5to 15% of such cases. Current recommendations provide that all patientspresenting with chronic prostatitis (both CBP and ACP) should be treatedinitially with antibiotics for 2 weeks and should receive continuedtreatment if symptoms improve. The choice of antibiotic can be critical,as the prostate and nearby seminal vesicles present a significant pHgradient. Thus, the chosen antibiotic should have sufficient chemicalstability over a range of pH (e.g., 7.2 to 8.0) while also exhibitingeffective penetration into the prostate gland. The zwitterionicfluoroquinolones such as ciprofloxacin (CIP) and levofloxacin havesurpassed older drug treatments for chronic prostatitis such astrimethoprin-sulfamethoxazole (TMP-SMZ) in both effective bacterialeradication and cost-effectiveness. A 500 mg dose of CIP administeredtwice a day for 28 days yielded bacteriological cure rates of 63-76% inclinical studies, whereas most studies on TMP-SMZ or TMP alone yieldedefficacy rates between 30-50% and required longer duration of therapy,such as 90 days. Significant room therefore still exists for improvementin the cure rate.

Some have advocated direct injection of antibiotics to the prostategland due to the relatively high failure rate of systemic antibioticadministration. The failure of oral antibiotics is mainly thought to bedue to an associated local autoimmune disease process and the possiblepresence of intraprostatic bacterial biofilms which resist drugpenetration, providing a therapeutic argument for local antibioticadministration. Guercini et al. (Arch Ital Urol Androl 77:87-92 (2005))have also demonstrated enhanced improvement in therapy with additionalco-administration of betamethasone, an immuno-suppressing steroidinfused in a cocktail solution with antibiotics, to the prostate inorder to counter the effects of the autoimmune disease process. In thatstudy, chronic prostatitis patients who had experienced repeated failureof oral antibiotics in the previous 12 months underwent prostaticinfiltration of antibiotics and betamethasone. In the study, 68% of thestudy participants were effectively cured, and 13% of the participantsshowed no response. While local prostate antibiotic injection has shownreasonable efficacy in clinical trials, it has not yet become a popularor widespread therapy in use among most urologists.

The seminal vesicles are a pair of coiled tubular glands which formlateral outpouchings of the ampulla of the vas deferens, which connectsthe epididymis of the testes to the prostate gland. The seminal vesiclesand the ampulla form the ejaculatory duct which empties into theprostate gland. Infection and inflammation of the seminal vesicles(vesiculitis) is uncommon in the United States, and it is usuallytreated with systemic antibiotics. Cancer originating in the seminalvesicles is rare, although secondary invasion of tumors from the nearbyprostate gland, bladder, or rectum is more common. One identifiedbrachytherapy treatment for prostate cancer with secondary seminalvesicle involvement includes the implantation of radioactive ¹⁰³Pdseeds.

Accordingly, a need exists to provide a local drug delivery device andmethod to replace multiple intraprostatic injections as a sustainedtreatment of antibiotics over an extended period. In addition, it wouldbe desirable to provide alternatives for treating vesiculitis, cancer,or other diseases and conditions involving the seminal vesicles,ampulla, prostate, and/or surrounding tissues, particularly in aminimally invasive manner for local delivery of one or more drugs.

It would be further desirable to provide treatments in which atherapeutically effective amount of drug can be administered over anextended period to one or more urological tissue sites without a strictor complicated dosing regimen. In addition, there is a need forcontrolled drug device that is suitable for delivery into and retentionin a genitourinary site in a patient, such as a seminal vesicle, vasdeferens, ejaculatory duct, or prostate. In particular, there is a needfor materials of construction that are functional for storing andreleasing drug, that are suitably elastic for minimally invasivedeployment and retention, and that do not require explantation followingcompletion of the drug release.

SUMMARY OF THE INVENTION

In one aspect, a method is provided for local controlled delivery of adrug to the seminal vesicle, the prostate, the ejaculatory duct, or thevas deferens of a patient in need of treatment. In one embodiment, themethod includes implanting a resorbable drug delivery device within theseminal vesicle, the prostate, the ejaculatory duct, or the vas deferensof the patient. The drug delivery device may include an elastic devicebody housing at least one drug reservoir which contains at least onedrug. In a preferred embodiment, the method further includes releasingthe drug (i.e., permitting the drug to be released) from the device in acontrolled manner to, typically directly to, the seminal vesicle, theprostate, the ejaculatory duct, or the vas deferens.

In one embodiment, the step of implanting the resorbable drug deliverydevice includes placement of a catheter in the urethra followed bycystoscopic deployment of the drug delivery device through the catheter.In another embodiment, the step of implanting the resorbable drugdelivery device includes transrectal injection. In various embodiments,the step of implanting the drug delivery device further includes imagingand positioning of the drug delivery device by transrectalultrasonography.

In various applications of the device and methods described herein, thepatient may present with chronic prostatitis, vesiculitis,post-prostatectomy complications, or a cancer involving the prostategland, bladder, or rectum.

In certain embodiments, the device body includes an elastomericpoly(glycerol-sebacic acid). In various embodiments, the release of thedrug in vivo is osmotically driven for at least a majority of the drugpayload that is released. In a particular embodiment, the device bodydegrades by surface erosion into biocompatible monomers, followingrelease of substantially all of the drug from the device body.

In one embodiment, a method is provided for local delivery of a drug toa genitourinary tissue site of a patient in need of treatment thatincludes implanting a resorbable drug delivery device within a tissuelumen at a genitourinary site of the patient. In an alternativeembodiment, implantation of the resorbable drug delivery device iswithin a non-lumenal genitourinary tissue site of the patient. The drugdelivery device may include an elastic device body housing at least onedrug reservoir which contains at least one drug. The step ofimplantation may include insertion of the device through a bore of ahollow needle or cannula. The method also includes permitting the drugto be released from the device in a controlled manner to thegenitourinary site.

In another aspect, a method is provided for making an implantable drugdelivery device. The method includes providing a pre-polymer for forminga biocompatible, resorbable elastomer; extruding or molding thepre-polymer into a device body having an elongated shape which comprisesa first end, an opposed second end, at least one sidewall between thefirst and second ends and a hollow bore defined by the at least onesidewall; polymerizing the pre-polymer to produce a cross-linkedelastomeric polymer; loading a drug formulation into the hollow bore;and closing off the hollow bore at positions to contain the drugformulation therein to form an implantable drug delivery device, whichis dimensioned and has an elasticity suitable for deployment of the drugdelivery device via urethral catheterization or transrectal injectioninto and retention in a genitourinary site in a patient.

In another aspect, an implantable medical device is provided thatincludes a resorbable, elastic device body having at least one elongatedsidewall and at least one payload reservoir defined therein. The devicebody provides in vivo controlled release of a payload which may bestored in the payload reservoir. The implantable medical device isdimensioned and has an elasticity suitable for deployment of the medicaldevice via urethral catheter or transrectal injection into and retentionin a genitourinary site in a patient. In certain embodiments, the deviceis dimensioned and has an elasticity suitable for deployment into andretention in a seminal vesicle, ejaculatory duct, prostate, or vasdeferens in a patient.

In various embodiment, the resorbable, elastic device body includes anelastomeric polymer. In some embodiments, the elastomeric polymer is ahydrophobic elastomeric polyester, such as a poly(glycerol-sebacicacid). In some embodiments, the elastomeric polymer includes apoly(caprolactone), a polyanhydride, an amino alcohol-based poly(esteramide), or a poly(octane-diol citrate).

In various embodiments, the device may provide controlled release of thepayload in vivo by osmotic pump action, diffusion, surface erosion ofthe device body or a part thereof, or a combination of these mechanisms.

The device body may include one or more apertures. In some suchembodiments, the sidewalls are selectively permeable to water andessentially impermeable to the payload. In further such embodiments,release of the payload from the device in vivo is osmotically driven. Insome embodiments, the diameter of each of the one or more apertures isbetween about 20 and about 300 μm. In further such embodiments, thedevice includes a degradable membrane in register with at least one ofthe one or more apertures. For example, release of payload from thereservoir through the aperture is delayed until the membrane hasdegraded in vivo. Degradation of the membrane in vivo would occur, in atypical embodiment, before degradation of the device body in vivo.

In one embodiment, release of the payload from the device in vivo occursby diffusion through one or more apertures in the device body, thesidewall of the device body, or a combination thereof. In anotherembodiments, release of the payload from the device in vivo occurs bysurface erosion of the device body. In one case, such an erodible devicebody may comprise an erodible matrix material with at least one drug,which may be dispersed in the matrix material.

In preferred embodiments, the payload includes at least one drug. Invarious embodiments, the drug includes an antibiotic agent, animmunosuppressant, an anti-inflammatory agent, a chemotherapeutic agent,a local anesthetic, or a combination thereof. In a preferred embodiment,the drug in the payload reservoir is in a solid form or semi-solid form.

In a certain embodiment, the device is sized and shaped to fit into a 14to 18 gauge transrectal needle. In another certain embodiment, thedevice is sized and shaped to fit into a 16 to 18 French urethralcatheter. In another embodiment, the device is configured to be passedthrough a catheter and is capable of being urged through the catheter bya stylet.

In certain embodiments, the device body has an outer diameter betweenabout 0.6 mm and about 3 mm. In one embodiment, the device body has alength between about 1 cm and about 7 cm. In one embodiment, thesidewalls have a thickness between about 100 μm and about 600 μm.

In one embodiment, the device body includes two or more discrete payloadreservoirs. These may be defined by the sidewalls and at least onepartition.

In one embodiment, an implantable drug delivery device is provided thatincludes a resorbable, elastic device body having at least one elongatedsidewall, at least one drug reservoir defined therein, and at least onedrug formulation in the drug reservoir. The device body may include ahydrophobic elastomeric polyester which degrades in vivo by surfaceerosion. The device body preferably provides controlled release of thedrug in vivo. In a preferred embodiment, the implantable drug deliverydevice is dimensioned and has an elasticity suitable for deployment ofthe drug delivery device via urethral catheter or transrectal injectioninto and retention in a seminal vesicle, prostate, ejaculatory duct, orvas deferens in a patient. In one embodiment, the hydrophobicelastomeric polyester comprises or consists of a poly(glycerol-sebacicacid). In a preferred embodiment, the device body includes at least oneaperture and provides controlled release of the drug in vivo by osmoticpressure.

An osmotic pump device may include a housing and a drug contained in thehousing. The housing may be made of a bioresorbable elastomer and mayhave at least one aperture. The pump device may be configured todispense the drug in vivo, driven by osmotic pressure, through the atleast one aperture. In particular embodiments, the bioresorbableelastomer comprises a poly(glycerol-sebacic acid). In a preferredembodiment, the osmotic pump device is dimensioned and has an elasticitysuitable for deployment into and retention in a seminal vesicle,prostate, ejaculatory duct, or vas deferens in a patient.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a side cross-sectional view of the male genitourinary system.

FIG. 2 is a front, partial cross-section view of a portion of the malegenitourinary system.

FIG. 3 is schematic cross-sectional view of an embodiment of a drugdelivery device.

FIG. 4 is schematic cross-sectional view of another embodiment of a drugdelivery device that functions as an osmotic pump.

FIG. 5 is a block diagram illustrating an embodiment of a method ofdelivering a drug to a genitourinary site.

FIG. 6 is a series of side cross-sectional views of the malegenitourinary system, illustrating a method of implanting a drugdelivery device via urethral catheterization.

FIG. 7 is series of side cross-sectional views of the male genitourinarysystem, illustrating a method of implanting a drug delivery device viatransrectal injection.

FIG. 8 is a block diagram illustrating an embodiment of a method ofmaking a drug delivery device.

FIG. 9 is a schematic perspective view of a prototype drug deliverydevice tested in vitro.

FIG. 10 is a graph demonstrating an experimental drug release profilefor an in vitro experiment performed with a PGS module having a 100 μmorifice.

FIG. 11 is a graph of tabulated drug release results for orifices ofvarious sizes.

FIG. 12 is a graph of the tabulated drug release results for orifices ofvarious sizes as shown in FIG. 11, corrected for variations in modulethickness.

FIG. 13 illustrates a non-resorbable device used in an experimentconducted in vivo in rabbit.

FIG. 14 is a graph illustrating lidocaine plasma concentration over timefor the experiment conducted in vivo in rabbit.

DETAILED DESCRIPTION OF THE INVENTION

Devices and methods have been developed for delivery of a drug to one ormore sites of the male genitourinary system, such as the seminalvesicle, the prostate gland, the vas deferens, or the ejaculatory duct.In one embodiment, a device is wholly implanted in a portion of the malegenitourinary system to provide drug delivery at the implantation siteand surrounding tissues, particularly over an extended period of time,for example a time period of about two days to about four weeks. Forexample, the device may be dimensioned and may have an elasticitysuitable for deployment of the medical device via urethralcatheterization or transrectal injection into and retention in agenitourinary site, such as a seminal vesicle, ejaculatory duct, orampulla in a patient. The device may release one or more drugs. Forexample, the device may provide controlled release of the drug in vivo,such as by osmotic pressure.

FIG. 1 is a side cross-sectional view of the male genitourinary system100, and FIG. 2 is a front, partial cross-section view of the malegenitourinary system 100. As shown, the system 100 generally includesthe prostate gland 102, seminial vesicles 104, vas deferens 106, theejaculatory duct 108, the urethra 110, the bladder 112, and testes 114.The prostate gland 102 surrounds the urethra 110 just below the bladder112. The seminal vesicles 104 are a pair of coiled, tubular glands thatinclude inner ducts or lumens and outer pouches surrounding the lumens.The pouches are lined by columnar epithelium with goblet cells, as shownin FIG. 2. The gland is encased in a thin layer of smooth muscle andheld in a coiled configuration by loose adventitia. The seminal vesicles104 form lateral outpouchings of the ampulla 116 of the vas deferens106. The vas deferens 106 are tortuous ducts that connect the epididymisof the testes 114 to the ejaculatory duct 108. The seminal vesicles 104and the ampulla 116 of the vas deferens 106 are located posterior to thebladder 112 and are separated from the rectum by Denonvilliers' fascia,as shown in FIG. 1. In the adult human male, each seminal vesicle 104 isnormally about 5-10 cm in length and about 3-5 cm in diameter, with anaverage volumetric capacity of about 13 mL, while inner ducts or lumensthrough the seminal vesicles 104, the vas deferens 106, and theejaculatory duct 108 may be about 1-6 mm in diameter, as shown in FIG.2. For example, inner ducts through the ampulla 116 may be about 2-6 mmin diameter, inner ducts through the vas deferens 106 may be about 3-5mm in diameter, and inner ducts through the ejaculatory duct 108 may beabout 2 mm in diameter or less.

In one aspect, an implantable medical device is provided that isdimensioned and has an elasticity suitable for deployment into andretention in a genitourinary tissue site in a patient. In oneembodiment, the device includes a (i) resorbable, elastic device bodyhaving at least one elongated sidewall and at least one payloadreservoir defined therein; and (ii) a payload stored in the payloadreservoir. In one embodiment, the sidewall of the device body isselectively permeable to water and impermeable to the payload. In aparticular embodiment, the implantable medical device is dimensioned andhas an elasticity suitable for deployment into and retention in aprostate, a seminal vesicle, an ejaculatory duct, or a vas deferens in apatient. In one embodiment, the device is sized and shaped to fit into a14 gauge needle. In another embodiment, the device is configured to bepassed through a catheter, such as a urethral catheter, a cannula, or acystoscope. For example, the device may be capable of being urgedthrough a catheter or cannula by a stylet. In one example, the devicebody is configured for passage through an at least 16 Fr Foley catheter.In one case, the device may be in a folded configuration for passagethrough the catheter.

In another aspect, an osmotic pump device is provided that has a housingmade of a bioresorable elastomer and at least one aperture, and a drugcontained in the housing. The bioresorable elastomer may be or include apoly(glycerol-sebacic acid) (“PGS”). In one embodiment, the osmotic pumpdevice is dimensioned and has an elasticity suitable for deployment intoand retention in a seminal vesicle, ejaculatory duct, vas deferens, orampulla in a patient.

In one embodiment, the device body is in the form of an elongated hollowtube. In one example, the device body has an outer diameter betweenabout 0.6 mm and about 3 mm, such as between about 1 mm and about 1.5mm; and has a length between about 1 cm and about 7 cm, such as betweenabout 1 cm and about 1.5 cm. In this or other examples, the sidewall ofthe device body may have a thickness between about 100 μm and about 600μm, such as between about 400 μm and about 600 μm.

In one embodiment, the device body is in an elongated shape, such as atube. It may have an exterior profile that is substantially cylindrical,with ends being both rounded, both flat, or a combination of these andother configurations. The device body also may have a more complexprofile to facilitate its retention at the site of deployment. Forexample, the shape of the device body may include a portion tapered inan axial direction. For instance, the device may have a bullet, torpedo,or conventional suppository shape. The device body may also be ringshaped or annular shaped. The device should not add significantresistance to the passage of the seminal fluid and its constituents whenimplanted in the genitourinary site, such as the seminal vesicle,ejaculatory duct or ampulla.

The device body preferably is small and elastic. Such a configurationpermits inserting the device body into an administration device, such asa catheter of a urethral cystoscope or a transrectal needle. Theelasticity of the device also permits the device body to conform to theinner structures of the implantation site, such as the seminal vesicle,the ejaculatory duct or the vas deferens (e.g., ampulla). Thus,irritation to the tissues at the implantation site may be reduced.

In one embodiment, the device body is comprised of two or more elongatedsegments connected together. For example, the segments may be coupled inaxial alignment by a flexible tether.

In various preferred embodiments, the resorbable, elastic device body isformed of or includes an elastomeric polymer, i.e., an elastomer. In oneembodiment, the elastomeric polymer comprises a hydrophobic elastomericpolyester.

In a preferred embodiment, the polymer is a biocompatible condensationpolymer of glycerol and a diacid, such as described in U.S. PatentApplication Publication No. 2003/0118692 to Wang et al., which isincorporated herein by reference. In one preferred embodiment, theelastomeric polymer comprises a poly(glycerol-sebacic acid). Itadvantageously has the combination of physical, chemical, and mechanicalproperties for forming the device bodies described herein, including: 1)degradation via hydrolysis of ester bonds into alcohol and acidmonomers; 2) crosslinking bonds identical to those in the polymerbackbone; 3) non-toxic monomers, one with tri-functionality to providecrosslinking capability and one with hydroxyl groups to provideadditional mechanical stability via hydrogen bonding. Glycerol, with itstri-functionality, hydroxyl groups, and biocompatibility, functions asthe primary building block for the synthesis of lipids in vivo. Sebacicacid, as the acid monomer, has a desirable chain length (i.e. longenough not to cyclize during polymerization and short enough to mix wellwith glycerol), functions as the natural metabolic intermediate inω-oxidation of fatty acid chains, and has been shown to be safe in vivo.Products containing both glycerol and sebacic acid have been approved bythe FDA for use in medical applications.

In alternative embodiments, the bioresorable elastomeric polymer maycomprise a poly(caprolactone) (PC) derivative, a poly(anhydride), anamino alcohol-based poly(ester amide) (PEA), or a poly(octane-diolcitrate) (POC), although synthesis of the polymer may have to beadjusted to achieve the desired biodegradation characteristics andelastic properties.

In various embodiments, the device body provides controlled release ofthe payload in vivo by dispensation through one or more apertures in thedevice body, by diffusion through the sidewalls, by surface erosion ofall or a portion of the device body, or a combination thereof.

In some embodiments, the device body includes one or more apertures thatfunction as release orifices. The aperture may be at an end of thedevice body or in a side wall of the device body, or a combinationthereof. Two or more discrete apertures may be provided in selectedpositions through the outer surface of the device body. The aperturesmay be formed by, for example, precision machining, mechanical punching,laser drilling, or by molding. The apertures may be microscale in size,which may be required for effective osmotic release of drug from thepayload reservoir. The apertures may also be one or more open ends of anelongated housing in communication with a payload reservoir formed inthe interior of the housing. The size of the device can influence ordetermine the release kinetics. In one embodiment, the diameter of theone or more apertures is between about 20 μm and about 300 μm. In oneparticular embodiment, the diameter of the one or more apertures isbetween about 80 μm and about 170 μm. In one further embodiment, thediameter of the one or more apertures is between about 100 μm and about150 μm. In one optional embodiment, the apertures initially are sealeduntil a time after the device is implanted in the patient. For example,the device body may include a degradable membrane in register with atleast one of the one or more apertures, wherein the membrane degrades invivo at a faster rate than the device body and/or the membrane degradesin vivo enough to rupture before the device body can degrade enough torupture.

In a preferred embodiment, release of the payload from the device invivo is osmotically driven. For example, a majority of the drug, such asfrom about 60% to about 95% of the drug, is released in a controlledmanner with an osmotic pressure driving force. Advantageously, thisrelease mechanism is particularly suitable for drug delivery in the malegenitourinary tract. The reason for this suitability is that the osmoticmechanism provides release at a constant rate in physiological systemsinvolving significant pH gradients, such as the male genitourinarytract, because osmotic pressure is a constant driving force independentof changes in pH. In another embodiment, a majority of the drug may bereleased by an osmotic pressure mechanism in combination with anotherrelease mechanism, such as diffusion. For example, osmotic pressure maydrive the drug release during an initial delivery period, whilediffusion may augment or dominate the drug release thereafter. In onesuch embodiment, about 30% of the drug is released due to osmoticpressure during an initial delivery period, while the remainder of thedrug is released due to osmotic pressure and diffusion thereafter. Inanother embodiment, release of the payload from the device in vivooccurs primarily or entirely by diffusion. In some embodiments, thepredominate release mode may change over time following in vivoimplantation, for example, as the drug reservoir is depleted of drug, asthe device body disintegrates, or a combination thereof.

The payload reservoir or drug reservoir may be a hollow space within aninterior of the device body, defined by an interior surface of thedevice body wall. For example, the reservoir may be a central bore in anelongated annulus shaped device. In some cases, the device may includetwo or more separate payload reservoirs. For example, the otherwisecontinuous bore within a single device body may be segregated intodiscrete compartments by one or more partitions perpendicular to theaxis of the annulus. In another example, the device body may havemultiple lumens. These may be arranged side-by-side, e.g., made by anextrusion process.

In a preferred embodiment, the payload in the device body comprises oneor more drugs. The drug may be a chemical or a biologic. Alternatively,the payload may deliver a substance other than a drug, such as adiagnostic agent or a placebo. Two or more drugs may be stored togetherin a single reservoir. Alternatively, two or more drugs may be stored intwo or more separate reservoirs in a single device.

In some preferred embodiments, the one or more drugs are useful fortreating chronic prostatitis, seminal vesiculitis, post-prostatectomycomplications, or cancer, such as a cancer of the prostate gland, thebladder, the rectum, or surrounding areas including the seminalvesicles. In one embodiment, the drug comprises an antibiotic agent,such as a fluoroquinolone. In a preferred embodiment, thefluoroquinolone comprises ciprofloxacin or levofloxacin. In some otherembodiments, the drug comprises an immunosuppressant, ananti-inflammatory agent, a chemotherapeutic agent, a local anesthetic,an alpha-blocker, or a combination thereof. Other drugs also may beincluded in the device. The drug may be in a substantially pure form orformulated with one or more pharmaceutically acceptable excipients,which are known in the art.

The drug formulation may be in a concentrated or pure form, such as asolid, semi-solid, or gel, so as to contain in as small a volume aspossible enough drug for release over the extended period required for aparticular therapeutic indication. The solid form may be a compactedpowder. The drug may be in a lyophilized form. In other embodiments, thedrug may be in the form of a pure liquid, a suspension, emulsion, orsolution.

In one embodiment, the drug is in the form of a hydrochloride or otherpharmaceutically acceptable salt. For example, the hydrochloride saltform of the ciprofloxacin has a significantly higher water solubilitythan the plain form, which makes the salt form more suitable as anosmotic agent for an osmotic pump device. In one embodiment, the drug orother payload substance has a water solubility between about 30 andabout 300 mg/mL at 37° C.

In one particular embodiment, an implantable drug delivery device isprovided which is dimensioned and has an elasticity suitable fordeployment via urethral catheter or transrectal injection into andretention in a seminal vesicle, ejaculatory duct, or vas deferens (e.g.,ampulla) in a patient, wherein the device includes (i) an elongated,resorbable, elastic device body housing at least one drug reservoir andbeing composed of a hydrophobic elastomeric polyester which degrades invivo by surface erosion, for example with a disintegration half life ofbetween about 1 week and 6 weeks; and (ii) at least one drug formulationin the drug reservoir, wherein the device provides controlled release ofthe drug in the seminal vesicle, ejaculatory duct, or vas deferens. Thedevice body may include at least one aperture and may have side wallsthat are water permeable and selectively permeable to the drug, suchthat the device provides osmotically controlled release of the drugdispensed from the at least one aperture. In a preferred embodiment, thehydrophobic elastomeric polyester includes or consists essentially of apoly(glycerol-sebacic acid).

For example, FIG. 3 is a cross-sectional view of an example embodimentof a drug delivery device 300. As shown, the drug delivery device 300includes a device body 302 or housing that defines a reservoir 304 orinner core. The device body 302 is configured to retain or hold a drug306 or other payload in the core or reservoir 304 for release into animplantation site over an extended period of time. The drug 306 orpayload may be released through one or more apertures 308 or releaseorifices in the sidewall of the device body. In addition, one or moreplugs 310 or stops are provided to impede the drug 306 from escapingthrough ends of the device body 302.

The device body 302 and reservoir 304 may have any suitable shape orconfiguration. For example, the illustrated device body 302 andreservoir 304 are both substantially cylindrical in shape. Particularly,the device body 302 includes a generally tubular sidewall that definesgenerally cylindrical exterior and interior surfaces. The interiorsurface of the sidewall defines the boundary of the reservoir 304 orcore, which is substantially hollow or empty for loading with the drug306 or payload. The apertures 308 or release orifices, if any, may beformed through the sidewall, extending from the exterior surface to theinterior surface. The apertures 308 may also be defined by open endportions of the device body 302. The device body 302 also may be closedalong the open end portions by one or more plugs 310 or stops. The plugsor stops 310 may prevent any drug 306 within the core 304 from escapingthrough end portions. The plugs 310 or stops may have a range ofconfigurations. For example, the plugs 310 or stops may be smallobjects, such as spheres, discs, or balls, that substantially span thecross-section of the core 304. Example materials that may be used toform the plugs 310 include bioresorbable polymers of the type describedbelow, or other materials such as stainless steel. In preferredembodiments, the plugs 310 may be slightly larger in cross-section areathan the cross-sectional area of the core 304. In such embodiments, thedevice body 302 may frictionally engage the plugs 310 to hold them inplace. In some embodiments, plugs 310 or stops may also be positionedalong the length of the core 304 to divide the core into multiplediscrete reservoirs 304, which may be loaded with the same or differentdrugs 306. In such embodiments, multiple discrete apertures 308 may belocated along the length of the device body 302 such that at least oneaperture is associated with each of the reservoirs 304. It should benoted that the apertures 308 may also be formed through one or more ofthe plugs 310 in some embodiments. The illustrated embodiment is merelyone example of a shape and configurations that may be employed, as aperson of skill in the art could envision a variety of otherconfigurations.

In one embodiment, the device body 302 has no associated retentionfeatures. In this case, the device body 302 is retained at thedeployment site in vivo through frictional engagement with surroundingtissue of the site, such as the seminal vesicle, prostate, vas deferensor ejaculatory duct. For example, the device body 302 may be at leastpartially embedded within tissue of the deployment site in vivo. Asanother example, the device body 302 may be at least partially implantedwithin a lumen of the deployment site in vivo, and at least a portion ofthe outer surface of the device body 302 may contact or engage at leasta portion of the inner surface of the lumen to create friction. In suchcases, at least a portion of the device body 302 may have across-sectional area or shape that exceeds or differs from the normalcross-sectional area or shape of the lumen, facilitating the creation offriction. The tissue in the implantation site may expand to permitinsertion of the device via catheter or injection, and once implantedthe tissue may relax or return to hold the device 302 in place withinthe lumen.

In other embodiments, the device body 302 may be configured forretention within the deployment site in vivo. For example, the devicebody 302 may have one or more retention features. In embodiments, thedevice body 302 may optionally have an elastic retention frame, whichretains the device in a genitourinary site. The retention frame may havea number of shapes for retention, including hoop, coil, spring, 2-Dspiral, or 3-D spiral shapes. In other embodiments, the device body 302itself may have one or more of these shapes. The device body 302 mayalso be associated with separate retentive features. For example, thedevice body 302 may be a linear shape with flexible and extendibleprojections, anchor-like structures such as wings or legs, or structuresthat change shape or configuration to assume a lower-profile shape forinsertion and a higher-profile shape upon implantation. These retentivefeatures may be included but typically would be omitted for devicesintended for deployment in other lumenal tissue sites, such as theseminal vesicle, ejaculatory duct, or the ampulla, or in non-lumenaltissue sites.

The material used to form the device body 302 may be selected so thatthe device body 302 is one or more of the following: elastic,biocompatible, resorbable, suitably mechanically and structurally sound,and at least partially permeable. A device body 302 that is elastic maybe suited for inserting through a bore of a catheter or a needle into apatient and for retention in the patient without significant irritationor discomfort. Such a device body 302 may stretch and deform during andafter implantation, without experiencing unsuitable yielding or failurethat impacts drug delivery. The elasticity may be achieved by formationof the device body from an elastomeric polymer (i.e., an elastomer). Adevice body 302 that is biocompatible may be tolerated by the patientthroughout the duration of implantation. A device body 302 of suitablemechanical strength and structural integrity may facilitate reliable andconsistent drug release throughout the duration of therapy. A devicebody 302 that is resorbable may naturally degrade or erode in time,eliminating the need for removal or extraction. In some embodiments, thedevice body 302 may begin degrading or eroding once implanted in thebody, yet the configuration of the device body 302 may be such that thedevice body 302 maintains suitable mechanical strength and integrityover the duration of therapy. Such a configuration may be obtained byselecting the materials and dimensions of the device body 302 in view ofthe intended implantation site and duration of therapy. For the purposeof this disclosure, the term “duration of therapy” indicates the periodof time over which a drug 306 is emitted from the device 300, while theterm “duration of implantation” indicates the period of time over whichthe device 300 is implanted in the body before completely eroding. Theduration of implantation may exceed the duration of therapy, so that thedrug is substantially completely released from the device 300 before thedevice 300 experiences an unsuitable degree of erosion.

A device body 302 that is at least partially permeable may be suited forgenerating an osmotic pressure in the core or reservoir 304, permittingthe device 300 to operate as an osmotic pump. In a preferred embodiment,the device body 302 is permeable to water or other fluid withoutdissolving, degrading, or swelling in response to the presence of wateror other fluid, which may facilitate implanting the device 300 forrelease of the drug 306 over an extended time period, without the devicefailing, at least without failing prior to completion of the intended,controlled drug delivery functionality.

In one embodiment in which the device body 302 is at least partiallypermeable, the device 300 operates as an osmotic pump. Particularly, thedevice body 302 may be selectively permeable to water or other bodilyfluids so that such fluids may permeate through the device body 302 tothe reservoir 304. Once in the reservoir 304, the fluid may solubilize adrug 306 or payload housed therein. The fluid may create an osmoticpressure in the core or reservoir 304 to drive the drug 306 or payloadfrom the device body 302, such as through any apertures 308. In apreferred embodiment, the device body 302 is suitably permeable to waterwhile being substantially or negligibly impermeable to the drug 306 inthe reservoir 304. In such embodiments, the device 300 may be suited tofacilitate a controlled, substantially constant release of the drug 306throughout at least a substantial portion of the duration of therapy.Such a device body 302 may be semi-permeable or “permselective.”

In preferred embodiments in which the device body 302 operates as anosmotic pump, the drug 306 is released through the apertures 308. Theapertures 308 may also permit release of the drug 306 in otherembodiments, such as those in which the device 300 operates viadiffusion. The size, shape, and location of the apertures 308 may atleast in part determine the release profile for the drug 306. Thus, thesize, shape, and location of the apertures 308 may be selected toachieve a desired release profile in some embodiments, along with thematerial used to form the device body 302, the shape and dimensions ofthe device body 302, the characteristics of the drug 306, theimplantation site, and the intended duration of therapy. In someembodiments, the device 300 further includes one or more degradablemembranes. The degradable membranes may initially be in registrationwith at least one of the one or more apertures 308. Once implanted, thedegradable membranes may degrade more quickly than the device body 302to permit release of the drug 306.

One type of material that can be used to form the device body 302 is anelastomeric polymer, such as a poly(caprolactone), a polyanhydride, anamino alcohol-based poly(ester amide), or a poly(octane-diol citrate).Other suitable materials for the device body 302 include hydrophobicpolymers that degrade via surface erosion, such as polyorthoesters, orbiocompatible and resorbable materials, such as polyactide,polyglycolide and their coploymers (PLA, PGA and PLGA). Still othermaterials, or combinations of these and other materials, may be used forthe device body 302.

One particularly suitable material is a hydrophobic elastomericpolyester that degrades by surface erosion, such aspoly(glycerol-sebacic acid) (“PGS”). PGS is generally elastic,biocompatible, resorbable, suitably mechanically and structurally sound,selectively permeable, and hydrophobic. Particularly, PGS may degrade invivo by surface erosion into biocompatible monomers, yet PGS maymaintain mechanical strength and integrity even after the experiencingsignificant erosion. For example, PGS implanted in vivo in rat has beenshown to have a half-life of about three weeks while retaining about 75%of its original mechanical strength. When formed from PGS, the devicebody 302 may be configured such that the duration of therapy ends beforethe device body has eroded to the point of substantial mechanicalimpairment or failure. Additionally, a device body 302 formed from PGSmay not experience significant swelling or induce the formation ofsignificant fibrous capsules in the body once implanted.

In embodiments in which the device body 302 erodes or degrades in vivo,it generally is not be necessary to configure the device body 302 forretrieval. For example, the device body 302 may lack retrieval features,such as rings, springs, coils, or pigtails, that facilitate grasping thedevice body 302. Also, retrieval may not be a significant factor, or maybe ignored completely, when selecting the geometry of the device body302. For example, a device body 302 that is relatively linear andsubstantially cylindrical may lack a retrieval feature and yet may besuited for implantation in a site such as a seminal vesicle, a vasdeferens, an ejaculatory duct, or a prostate.

The device 300 may be sized, shaped and configured for implantation intoa genitourinary site of a human male. For the purposes of this, the term“genitourinary site” is intended to connote any site within thegenitourinary system, including any portion of the prostate gland, theseminal vesicles, the vas deferens, the ejaculatory duct, the urethra,the bladder, and the testes. In preferred embodiments, the device 300 issized, shaped and configured for implantation within a lumen or duct ofthe genitourinary system, such as in a lumen or duct of one of theseminal vesicles, vas deferens, ejaculatory ducts, or the urethra. Thedevice 300 may also be sized, shaped and configured for embeddingdirectly within a non-lumenal tissue site of the genitourinary system,such as directly in the prostate gland or the tissues of the seminalvesicles. Due to its elastic nature, the device body 302 in such anembodiment may deform to fit the shape of the implantation site and maygive to permit the passage of bodily fluids through the implantationsite, such as seminal fluid or its constituents components. The elasticnature of the device 300 also may permit folding the device body 302 insome embodiments for implantation through a needle or cannula. Onceimplanted, the device 300 may naturally return following implantationinto an unfolded position.

In some embodiments, the device 300 is sized, shaped, and configured forimplanting into a patient through a bore of a hollow needle or cannula.For example, in embodiments in which the device is implanted in agenitourinary site, the device 300 may be implanted via urethralcatheterization as described in further detail below with reference toFIG. 6, or via transrectal injection as described in further detailbelow with reference to FIG. 7. Typical urethral catheters for adultmale patients are in the range of about 16 French to about 18 French,which corresponds to an outer diameter of about 5.3 mm to about 6.0 mm,while typical transrectal needles for adult male patients are in therange of about 14 gauge to about 18 gauge, which corresponds to an innerdiameter of about 1.07 mm to about 1.6 mm. Thus, the device may have anouter dimension that is less than about 4 mm for insertion via aurethral catheter or less than about 1.5 mm for insertion via atransrectal needle.

The length of the device 300 may be selected based in part on the sizeand shape of the implantation site and the amount of drug 306 to bedelivered. For example, a longer device 300 may have a larger reservoir304, which may permit implanting a larger payload and releasing largerdoses and/or the appropriate dosage of drug over longer sustainedperiod.

One example device 300 may have an outer diameter between about 0.6 mmand about 3 mm, such as between about 0.6 mm and about 1.6 mm, and alength between about 1 cm and about 7 cm, such as between about 1 cm andabout 1.5 cm. Such a device 300 may be suitable for insertion through acatheter or needle, such as a urethral catheter or a transrectal needle.Such a device may also be suited for implantation into a genitourinarysite of an adult male patient, such as a lumen or duct of through one ofthe seminal vesicles, vas deferens, or ejaculatory ducts. In these andin other embodiments, the sidewalls of the device body 302 may have athickness between about 100 μm and about 600 μm, such as between atleast about 200 μm and about 300 μm, and the apertures 308 may havediameters of between about 20 μm and about 300 μm, such as between about80 μm and 170 μm, or more particularly between about 100 μm and about150 μm. Such dimensioning of the sidewalls and apertures may facilitatezero-order release of the drug 306 from the core 304 via an osmoticpressure driving force, as further described below.

The device 300 may be configured to release a drug 306 through thesidewall, from the sidewall, through the orifice 308, or a combinationthereof. The device 300 may be configured to release the drug 306 viaosmotic pressure, diffusion, surface erosion, or a combination thereof.

In embodiments in which the device 300 is configured to release the drugin vivo via diffusion, the diffusion may occur through one or moreapertures 308, through the sidewall of the device body 302, or acombination thereof. Diffusion of the drug 306 may be driven by aconcentration difference between the drug 306 in the reservoir 304 andthe surrounding environment, such as the implantation site.

In embodiments in which the device 300 is configured to release the drugin vivo via surface erosion, the device body 302 may include one or morematrix materials. In one example, the one or more matrix materials maycomprise one or more synthetic polymers.

In another example, the one or more matrix materials may comprisebiodegradable, bioerodible, or water-soluble matrix materials. The drug306 may be distributed in the matrix material and the matrix materialmay degrade or dissolve in vivo to controllably release the drug. Insuch embodiments, the device 300 may or may not have a core or reservoir304. In other such embodiments, the device 300 may include a core orreservoir 304, in which case a bolus dose of the drug may be releasedafter the device body 302 degrades.

In embodiments in which the device 300 is configured to release the drug306 in vivo via osmotic pressure, the drug 306 may be released throughthe one or more apertures 308. An example is shown in FIG. 4. Once thedevice 400 is implanted in vivo, water or other bodily fluid 412 maypermeate through the device body 402, such as through the sidewall. Thewater or fluid 412 may dissolve the drug 406 in the core, forming asolution of the drug 406. The hydrostatic pressure within the core mayrise, which may expel the solution through the orifice 408.

Returning to FIG. 3, in embodiments, the device 300 may be configuredfor relatively zero-order release via osmotic pressure. For example, thedevice 300 may be configured to employ a substantially zero-orderrelease rate for at least a portion of the duration of therapy. In onepreferred embodiment, a majority of the drug load is released at a zeroorder rate. The term “zero-order release rate” indicates the drug 306 isreleased at a relatively constant rate. To achieve a zero-order releaserate, the size and number of the apertures 308 and the thickness of thesidewall of the device body 302 may be chosen, along with otherparameters of the device design. For example, each aperture 308 may besized so that the aperture 308 is small enough to reduce or eliminatebulk diffusion through the aperture 308, and yet is large enough torelieve hydrostatic pressure within the core 304, which otherwise maycause the device 300 to experience hydrostatic deformation. In one suchembodiment, the diameter of the one or more of the apertures 308 may bebetween about 20 and about 300 μm, and the thickness of the sidewalls ofthe device body 302 may be between about 100 μm and about 600 μm, sothat the sidewalls are thick enough to withstand the internalhydrostatic pressure in the core 304.

Such a device 300 may be suited for operating as an osmotic pump torelease one or more drugs into a genitourinary site of a patient. Anosmotic delivery mechanism may permit zero-order release rates inphysiological systems involving pH gradients, such as thegastro-intestinal tract or the genitourinary system, as changes in pHmay not impact osmotic pressure. Thus, a relatively constant drivingforce may expel the drug even in the presence of a pH gradient.

The release rate may also be at least partially dependent on thesolubility of the drug 306, formulation excipients, and the density(porosity) of the drug in the core 304. For example, the release mayinitially occur at a relatively zero-order rate, during which time thedevice 304 operates substantially via osmotic pressure, and subsequentlythe release may occur via, for example, a combination of osmoticpressure and diffusion. Drugs with lower solubility may have a higherpercentage released at a zero-order release rate, but may release moreslowly due to a lower osmotic pressure. Drugs having a higher solubilitymay release at faster rates, but a smaller percentage of the drugpayload may be released at a zero-order release rate. In certainembodiments, the solubility of the drug 306 in water is between about 30mg/mL and about 300 mg/mL at 37° C. For example, ciprofloxacin-HCl(CIP-HCl) has a solubility of about 0.03 g/mL, and in one embodimentexhibits zero-order release, driven by osmotic pressure, for about 97%of the drug. In another example, lidocaine-HCl (LIDO-HCl) has asolubility of about 0.68 g/mL and in one embodiment exhibits zero-orderrelease, driven by osmotic pressure, for about 32% of the drug. BecauseCIP-HCl has a lower solubility, however, the zero-order release rate forCIP-HCl may be lower than the zero-order release rate for LIDO-HCL.

In another aspect, methods are provided for delivering a payload to agenitourinary tissue site in a patient by deploying one of theimplantable medical devices described herein to a patient in needthereof. The term “patient” may include humans, such as an adult malehumans, or other mammals. The implantable medical device may beimplanted within a natural lumen within the genitourinary system, oralternatively the device may be implanted directly into a genitourinarytissue which is not at a lumenal site, e.g., the prostate gland.

In a certain embodiment, a method 500 is provided for local delivery ofa drug to a genitourinary site of a patient in need of treatment, suchas to the seminal vesicle, the ejaculatory duct, or the vas deferens(e.g., ampulla) of the patient. FIG. 5 is a block diagram of the method500. The method 500 includes, in block 502, implanting a resorbable drugdelivery device within the seminal vesicle, the ejaculatory duct, or thevas deferens (e.g., ampulla) of the patient, wherein the drug deliverydevice comprises an elastic device body housing at least one drugreservoir which contains at least one drug; and in block 504, permittingthe drug to be released from the device in a controlled manner to theseminal vesicle, the ejaculatory duct, or the ampulla.

In one embodiment, the step of implanting the resorbable drug deliverydevice in block 502 includes placement of a catheter in the urethrafollowed by cystoscopic deployment of the drug delivery device throughthe catheter. In an alternative embodiment, the step of implanting theresorbable drug delivery device in block 502 comprises transrectalinjection. In either of these cases, the step of implanting the drugdelivery device in block 502 may further include imaging and positioningof the drug delivery device, for example, by transrectal ultrasonography(“TRUS”), which is known in the art.

FIG. 6 is a series of side cross-sectional views of the malegenitourinary system, illustrating an embodiment of the step ofimplanting a drug delivery device via urethral catheterization. As shownin FIG. 6( a), a catheter 602 is placed in the urethra 604. The catheter602 extends to the implantation site, which may be a site within thegenitourinary system such as the prostate, the seminal vesicles, theejaculatory duct, or the vas deferens. Although catheterization throughthe urethra is typically employed to access the bladder, it is notedthat other portions of the anatomy may also be accessed along thisroute, as openings through the ejaculatory ducts into the seminalvesicles and the ampullae are accessible via the urethra. In certainembodiments, the catheter 602 is a 16-18 French unit Foley catheter. Asshown in FIG. 6( b), the drug delivery device 606 is inserted throughthe catheter 602 and is urged toward the implantation site using astylet 608. In certain embodiments, insertion of the device may beguided using a cystoscope, TRUS, or a combination thereof. As shown inFIG. 6( c), the catheter 602 is removed, leaving the device 606implanted for controlled release of the drug in vivo to the implantationsite and surrounding areas. Such an implantation step may be minimallyinvasive and may be performed in an outpatient setting, such as using alocal anesthetic.

FIG. 7 is series of side cross-sectional views of the male genitourinarysystem, illustrating an embodiment of the step of implanting a drugdelivery device via transrectal injection. As shown in FIG. 7( a), arectal ultrasound probe 702 is positioned in the rectum. The probe 702is positioned so that a transrectal needle 704 associated with a guide706 of the rectal ultrasound probe 702 can access the implantation sitethrough the anterior wall of the rectum. The implantation site may beany site within the genitourinary system, such as the prostate, theseminal vesicles, the ejaculatory duct, or the vas deferens. Althoughtransrectal needles are typically employed to access the prostatethrough the anterior rectum wall, it is noted that other portions of thegenitourinary system also may be accessed via this method, as theseminal vesicles, ampullae, and ejaculatory ducts lie adjacent to therectum near the prostate. The transrectal needle may be in the range ofabout 18-gauge to about 14-gauge, depending on the embodiment. As shownin FIG. 7( b), the drug delivery device 708 may be injected into theimplantation site using the transrectal needle 704. In one embodiment,injection of the device 708 is guided using TRUS. As shown in FIG. 7(c), the rectal ultrasound probe 702 and associated components areremoved, leaving the device 708 implanted for controlled release of thedrug in vivo to the implantation site and surrounding areas. Such animplantation step may be minimally invasive and may be performed in anoutpatient setting, such as using a local anesthetic.

With reference back to FIG. 5, the release of the drug in block 504 mayoccur over a time period of about 2 days to about 4 weeks. For example,the drug may be released over a period of about 2 weeks to about 3 weeksin some embodiments.

In a preferred method, following release of substantially all of thedrug in block 504, the device body degrades by surface erosion intobiocompatible monomers. For example, the device may begin degrading uponimplantation and may degrade while the drug is released. After the drugis released, the device may continue degrading to the point of loss ofmechanical integrity. For example, the device may degrade over a timeperiod of about 2 to about 8 weeks. In embodiments in which the drug isreleased over a time period of about 2 to about 3 weeks, the device maydegrade over a time period of about 4 to about 8 weeks. Thus, the method500 may further include permitting the device to degrade in vivo, whichmay avoid the need for removing or retrieving the device after the drughas been released. The method may be useful for example with a patientwho presents with chronic prostatitis, vesiculitis, post-prostatectomycomplications, or a cancer involving the prostate gland, bladder, orrectum.

In another aspect, a method 800 is provided for making an implantabledrug delivery device. FIG. 8 is a block diagram illustrating anembodiment of the method 800. In one embodiment, the method 900 includesthe steps of (i) providing a pre-polymer for forming a biocompatible,resorbable elastomer (block 802); (ii) extruding or molding thepre-polymer into a device body having an elongated shape which comprisesa first end, an opposed second end, at least one sidewall between thefirst and second ends and a hollow bore defined by the at least onesidewall (block 804); (iii) polymerizing the pre-polymer to produce across-linked elastomeric polymer (block 806); (iv) loading a drugformulation in the hollow bore (block 808); and (v) closing off thehollow bore at positions to contain the drug formulation therein (block810). The resulting implantable drug delivery device is dimensioned andhas an elasticity suitable for deployment via urethral catheterizationor transrectal injection into and retention in a genitourinary site in apatient. The method may further include forming one or more apertures inthe sidewalls of the device body. In various embodiments, the aperturesmay be formed by laser microablation, by drilling, by molding, or bymechanical punching. In one embodiment, the step of closing off thehollow bore comprises inserting at least one plug element into the firstend, the opposed second end, or both ends. The plug element may be madeof the same material as the device body, or it may be made of anothermaterial, such as a resorbable polymer.

In one process, the device body may be formed by casting andcross-linking of a pre-polymer under controlled conditions of vacuumand/or heat. In order to form a payload reservoir in the device body, awire may be positioned in the mold during the casting process. After thedevice body has cured, the device body may be removed from the mold andthe wire may be removed from the device body. Thereby, the hollowpayload reservoir is formed. In some cases, multiple device bodies maybe molded simultaneously. A module may be cast using multiple wires toform multiple hollow cores, and after the module is released from themold, the module may be cut into multiple device bodies. Thereafter, theorifice may be formed by, for example, laser microablation. In somecases, multiple orifices may be formed.

Alternatively, a high volume process can be used to make the device. Forexample, the device housing may be made extrusion, for example, onto acylindrical wire template or using an annular-shaped die.High-throughput laser drilling of the extruded body could follow, beforeor after loading of the payload and before or after cutting the extrudedbody to a specified length.

In another embodiment, another PGS casting method may be used to createthe device body. The PGS casting method may employ an elastic tubularmold, such as a length of silicone tubing. Melted polymer may be loadedinto the internal bore of the tubular mold, and a pin or wire may beinserted through the melted polymer. The pin or wire may have a head oflarger cross-sectional area than the cross-section of the bore. The pinor wire may be inserted through the bore until the head is inside thetubular mold. The tubular mold may then stretch about the head tomaintain the pin in position. On an opposite end of the tubular mold, awasher-type component having a hole for receiving the pin or wire may beslid along the pin or wire toward the tubular mold. The tubular mold maybe stretched to cover the washer-type component, such that the meltedpolymer fills the inner space of the tubing. Additional grips may beused to prevent accidental slipping or loosening.

Once cast, the device body may be removed from the tubular mold bycutting the tubular mold along its length. The geometry of the devicebody may be determined by the inner diameter of the tubular mold and thediameter of the pin or wire. The device body may then be loaded andplugged as described above.

The devices and methods described above will be further understood withreference to the following non-limiting examples.

Example 1 Making a Drug Delivery Device

A prototype PGS module for in vitro development was constructed andtested for drug release kinetics with ciprofloxacin, a fluoroquinolonecommonly prescribed for chronic prostatitis and other UTIs. Theprototype module 900 is shown in FIG. 9. The prototype module 900 wasrectangular in shape with an internal cylindrical core for housing a 300μm diameter drug rod 902 and contained a single 100 μm release orifice904. Modules were formed through melting of PGS pre-polymer within awire-strung aluminum mold followed by a polymerization reaction underheat and vacuum for 48 hours. The PGS casting remained within the moldas a laser microablation process drilled orifices at select locations onthe top surface of the casting, which projected down to the embedded 300μm diameter longitudinal wires.

Wires were pulled out of the mold through the sides and the PGS castingwas removed from the mold and cut into rectangular modules measuring 10mm×1.5 mm×1.5 mm, each with a single release orifice located in themodule mid-section. The single release orifice was produced by lasermachining.

The cast and cut PGS modules 900 were loaded with drug by insertingsolid-packed ciprofloxacin rods 902 into the hollow bore of the PGSmodules 900 (i.e., the device body). Then, the bore was plugged withstainless steel wire 906 to seal the drug 902 inside the PGS device body900.

Example 2 In vitro Release Kinetics of the Drug Delivery Device

For in vitro measurement of release kinetics, prototype PGS devicesloaded with ciprofloxacin were made as described in Example 1, weremounted on the inside of a glass vial, and were immersed in 2 mLde-ionized water. Time point measurements of ciprofloxacin-HCl (CIP)concentration in the surrounding media were taken roughly every 12 hoursover an 8-10 day period using a quantitative HPLC-UV detection methoddeveloped for CIP.

FIG. 10 illustrates the results of a representative CIP releaseexperiment for two PGS modules having a 100 μm orifice and a controlmodule without an orifice. The payload for each module is noted in μg.An induction time was observed before the onset of zero-order controlledrelease kinetics during which time water permeated into the devices andbegan to dissolve some of the drug payload. The two modules having 100μm orifices were observed to release CIP at nearly the same rate afterinduction even though one of the modules contained nearly three timesthe payload of the other. As shown, the release profile of the 100 μmmodule having the smaller payload began to flatten once its CIP contentsbecome fully dissolved and subsequently depleted. Diffusion of CIPthrough the PGS wall was not significant, as indicated by the resultsfor the control module, which lacked a release orifice.

The experiment was repeated for a number of modules having releaseorifices of different sizes and initial drug payloads of differentmasses. FIGS. 11 and 12 illustrate the results of these experiments. Foreach module, orifice diameter is noted in μm and initial drug payload isnoted in μg. FIG. 11 illustrates the actual release profile for eachmodule, from an initial time point, which corresponds to onset of drugrelease after an induction period, to an end time point, whichcorresponds to a release of 90% of the total drug payload. FIG. 12illustrates the same release profiles standardized or corrected forvariations in wall thickness along the module. Particularly, the releaseprofiles were multiplied by the average PGS wall thickness measured forthe corresponding module.

As shown in FIG. 11 and FIG. 12, the PGS modules having 100 and 150 μmorifices demonstrated zero-order release of CIP due to osmotic pressure.As shown in FIG. 11, release from these modules demonstrated arelatively linear relationship with respect to time for most of the drugmass released from each module. The release rate for these modulesremained roughly constant over time during release of up to 90% of thedrug payload, as shown in FIG. 12. The release rate then decreased asthe payload becomes fully dissolved, as seen in the leveling of theprofiles in FIG. 11 as the devices approached completion of theirpayload release. The release rate for the modules with 100 and 150 μmorifices was relatively independent of initial payload for most of thedrug mass released, as the release rates for different module wereroughly the same even though some modules had 2-3 times the payload ofothers.

The release rate from modules have 300 μm orifices appeared to bedependent on payload, as initial release rates varied among moduleshaving different drug payloads. The shapes of the release rate profilesfor most of the modules having 300 μm orifices, with the possibleexception of the module having the 427 μg payload, suggest that the drugwas released due to a combination of osmotic and diffusion releasemechanisms, as these release profiles appear significantly less linearthan the release profiles for devices having 100 μm and 150 μm orifices.As shown in FIG. 12, the release rate for modules having 300 μm orificesdeclined over time during the majority of the payload release,suggesting that devices having 300 μm orifices do not permit osmoticcontrol for zero-order release kinetics by allowing payload-dependentdiffusion processes to occur.

FIG. 11 also suggests that modules having 150 μm orifices release CIP ata slightly faster rate than modules having 100 μm orifices. Thethickness (h) of a semi-permeable membrane is noted to have a directinverse relationship to drug release rate, as noted by osmotic pumptheory in EQ. 1.

$\begin{matrix}{{{Drug}\mspace{14mu} {release}\mspace{20mu} {rate}} = {\frac{M}{t} \equiv {\frac{A}{h}k\; \pi \; C}}} & {{EQ}.\mspace{25mu} 1}\end{matrix}$

-   -   where A=wall surface area, h=wall thickness, k=produce of        mechanical permeability and reflection coefficient, π=osmotic        pressure at saturation, and C=drug solubility

Wall thicknesses were measured for each module and were noted to bethinner for those modules having 100 and 150 μm orifices that expressedfaster release rates. FIG. 12 accounts for this variability, as therelease profile for each module was multiplied by the average of itsmeasured wall thicknesses. Modules with 150 μm orifices were shown torelease CIP at a comparable rate to modules with 100 μm orifices.Modules with orifices in the range of 70-90 μm demonstrated slowerrelease rates than modules with 100 μm orifices, particularly in thecase of modules with 70 μm orifices.

Thus, for modules having orifice sizes in the range of 70-90 μm, releaserate was not independent of orifice size and was no longer under theexclusive control of osmotic parameters—the orifice was too small toallow hydrostatic pressure relief and proper osmotic release function.For modules having orifices in the range of 100 μm and 150 μm, releaserate was independent of orifice size and was controlled by the thicknessand surface area of the semi-permeable polymer wall, the osmoticpressure of the drug core and the solubility of the drug in accordancewith osmotic pump drug release theory (EQ. 1). For modules havingorifices in the 300 μm range, the orifice was too large to inhibit bulkdiffusion effects, resulting in increased release.

The average measured release rate of CIP from a device having an orificein the 100-150 μm range was 2.5±0.4 μg/hr in an in vitro de-ionizedwater environment. This release rate could be increased by addingmultiple orifices with separated drug compartments, while the releaseduration could be prolonged by increasing the payload through the devicelength as needed for the requirements of the device therapy.

The dimensions of the device can be reduced to fit lengthwise within thecore of a 14 or higher gauge needle or to fold in half to fit within a16 Fr catheter. The osmotic pressure of the drug core can be increasedby co-formulation with an agent of higher osmotic activity, such assodium chloride, thus overcoming possible isotonic or hypertonic effectsof an in vivo environment.

Example 3 Delivery of Lidocaine to the Vesicular Gland of Rabbit

A pilot in vivo experiment was conducted with a non-resorbable siliconedevice implanted in the vesicular gland of a rabbit (2.7 kg, New ZealandWhite, male). The drug used was lidocaine and total loading was 2 mg.This experiment was designed to simulate the situation when the deviceis implanted in a location other than the bladder, such as the seminalvesicle for men. The non-resorbable device for a rabbit experiment isshown in FIG. 13, and lidocaine plasma concentration over the time isshown in FIG. 14.

Example 4 Method of Forming a Drug Delivery Device Body

A casting method was used to make a device body having a length of about7.62 cm, a hollow reservoir having a diameter of about 330 μm, a firstorifice located about 2.81 cm from a first end of the device, and asecond orifice located about 2.81 cm from a second end of the device.The orifices had a diameter of about 100 μm. Such a device was formed bycasting PGS in a mold with embedded steel wires. The mold had a lengthof about 7.62 cm. A number of steel wires were strung through the moldalong its length. Each wire had a diameter of about 330 μm. After thePGS was cast, orifices were laser drilled into the device bodies. ThePGS was removed from the mold and cut into individual device bodies.

In another example, a mold was provided for forming a number of devicebodies. The mold was an aluminum mold, and a PGS pre-polymer was placedtherein. Wires were inserted into the mold for forming the payloadreservoirs. The mold had a length of about 150 mm and the wires weremade of stainless steel. After baking, the cross-linked PGS was removedfrom the mold, cut into sections, and further processed to yield anumber of device bodies. Sealing balls were inserted to plug one end ofeach payload reservoir, with the other end being left open to form therelease orifice.

Example 5 Method of Making a Drug Rod and Associated Drug DeliveryDevice

A method of making a drug rod and associating the drug rod with adelivery device body, or housing, was tested.

The drug rod was cast using solid powder within a die. The die wasformed from silicone to facilitate expulsion of the packed drug rod andto maintain a sterile and transparent environment. A hole having adiameter of about 300 μm was formed through the die. The die was mountedon an aluminum base with an embedded wire, which penetrated the hole ofthe silicone die. The embedded wire (diameter of about 340 μm)penetrated the silicone casting to a height of about 3 mm. The CIPpowder was deposited on top of the silicone die and packed into the coreof the die using a steel wire (diameter of about 300 μm) secured withina wire gauge drill chuck. The compressed CIP expanded the diameter ofthe die core, forming a depot during the packing procedure. Upon exitingthe die, the drug rod had a diameter of about 300 μm and a length ofabout 1 mm to about 22 mm. The drug rod remained attached to the end ofthe packing wire, allowing for positioning the drug rod in the core of aPGS module held open by reverse clamped tweezers.

The drug rod was positioned in a drug delivery device. Specifically, aCIP drug rod was be positioned in a PGS device. The PGS device had alength of about 1 cm, and the CIP drug rod had a length of about 3-5 mmand a width of about 400-550 μm. The orifice had a diameter of about 103μm. The drug loaded housings was sealed with steel wire plugs.

Publications cited herein and the materials for which they are cited arespecifically incorporated by reference. Modifications and variations ofthe methods and devices described herein will be obvious to thoseskilled in the art from the foregoing detailed description. Suchmodifications and variations are intended to come within the scope ofthe appended claims.

1. A method for local delivery of a drug to the seminal vesicle, theprostate, the ejaculatory duct, or the vas deferens of a patient in needof treatment, comprising: implanting a resorbable drug delivery devicewithin the seminal vesicle, the prostate, the ejaculatory duct, or thevas deferens of the patient, wherein the drug delivery device comprisesan elastic device body housing at least one drug reservoir whichcontains at least one drug; and permitting the drug to be released fromthe device in a controlled manner to the seminal vesicle, the prostate,the ejaculatory duct, or the vas deferens.
 2. The method of claim 1,wherein the step of implanting the resorbable drug delivery devicecomprises placement of a catheter and in the urethra followed bycystoscopic deployment of the drug delivery device through the catheter.3. The method of claim 1, wherein the step of implanting the resorbabledrug delivery device comprises transrectal injection.
 4. The method ofclaim 1, wherein the step of implanting the drug delivery device furthercomprises imaging and positioning of the drug delivery device bytransrectal ultrasonography.
 5. The method of claim 1, wherein thepatient presents with chronic prostatitis, vesiculitis,post-prostatectomy complications, or a cancer involving the prostategland, bladder, or rectum.
 6. The method of claim 1, wherein the devicebody comprises an elastomeric poly(glycerol-sebacic acid).
 7. The methodof claim 1, wherein the release of the drug in vivo is osmoticallydriven for at least a portion of the drug released.
 8. The method ofclaim 1, wherein following release of substantially all of the drug, thedevice body degrades by surface erosion into biocompatible monomers. 9.A method for local delivery of a drug to a genitourinary tissue site ofa patient in need of treatment, comprising: implanting a resorbable drugdelivery device within a genitourinary site of the patient, wherein thedrug delivery device comprises an elastic device body housing at leastone drug reservoir which contains at least one drug; and permitting thedrug to be released from the device in a controlled manner to thegenitourinary site, wherein the step of implantation comprises insertionof the device through a bore of a hollow needle or cannula.
 10. A methodfor local delivery of a drug to a genitourinary site of a patient inneed of treatment, comprising: implanting a resorbable drug deliverydevice within a non-lumenal genitourinary tissue site of the patient,wherein the drug delivery device comprises an elastic device bodyhousing at least one drug reservoir which contains at least one drug;and permitting the drug to be released from the device in a controlledmanner to the genitourinary tissue site.
 11. An implantable medicaldevice comprising: a resorbable, elastic device body having at least oneelongated sidewall and at least one payload reservoir defined therein;and a payload stored in the payload reservoir, wherein the device bodyprovides controlled release of the payload in vivo and wherein theimplantable medical device is dimensioned and has an elasticity suitablefor deployment of the medical device via urethral catheter ortransrectal injection into and retention in a genitourinary site in apatient.
 12. The device of claim 1, wherein the device is dimensionedand has an elasticity suitable for deployment into and retention in aseminal vesicle, ejaculatory duct, prostate, or vas deferens in apatient.
 13. The device of claim 11, wherein the resorbable, elasticdevice body comprises an elastomeric polymer.
 14. The device of claim13, wherein the elastomeric polymer is a hydrophobic elastomericpolyester.
 15. The device of claim 14, wherein the hydrophobicelastomeric polyester is a poly(glycerol-sebacic acid).
 16. The deviceof claim 13, wherein the elastomeric polymer comprises apoly(caprolactone), a polyanhydride, an amino alcohol-based poly(esteramide), or a poly(octane-diol citrate).
 17. The device of claim 11,wherein the device body provides controlled release of the payload invivo by osmotic pressure, diffusion, surface erosion, or a combinationthereof.
 18. The device of claim 11, wherein the device body comprisesone or more apertures.
 19. The device of claim 18, wherein the sidewallsare selectively permeable to water and impermeable to the payload. 20.The device of claim 19, wherein release of the payload from the devicein vivo is osmotically driven.
 21. The device of claim 20, wherein thediameter of each of the one or more apertures is between about 20 andabout 300 μm.
 22. The device of claim 18, further comprising adegradable membrane in register with at least one of the one or moreapertures, wherein degradation of the membrane in vivo occurs morequickly than degradation of the device body in vivo.
 23. The device ofclaim 11, wherein release of the payload from the device in vivo occursby diffusion through one or more apertures in the device body, thesidewall of the device body, or a combination thereof.
 24. The device ofclaim 11, wherein release of the payload from the device in vivo occursby surface erosion of the device body, wherein the device body comprisesa matrix material having at least one drug.
 25. The device of claim 11,wherein the payload comprises at least one drug.
 26. The device of claim25, wherein the drug comprises an antibiotic agent, animmunosuppressant, an anti-inflammatory agent, a chemotherapeutic agent,a local anesthetic, or a combination thereof.
 27. The device of claim25, wherein the drug in the payload reservoir is in a solid orsemi-solid form.
 28. The device of claim 11, wherein the device is sizedand shaped to fit into a 14 to 18 gauge transrectal needle.
 29. Thedevice of claim 11, wherein the device is sized and shaped to fit into a16 to 18 French urethral catheter.
 30. The device of claim 11, whereinthe device is configured to be passed through a catheter and is capableof being urged through the catheter by a stylet.
 31. The device of claim11, wherein the device body has an outer diameter between about 0.6 mmand about 3 mm.
 32. The device of claim 11, wherein the device body hasa length between about 1 cm and about 7 cm.
 33. The device of claim 11,wherein the sidewalls have a thickness between about 100 μm and about600 μm.
 34. The device of claim 11, wherein the device body comprisestwo or more discrete payload reservoirs, which are defined by thesidewalls and at least one partition.
 35. An implantable drug deliverydevice comprising: a resorbable, elastic device body having at least oneelongated sidewall and at least one drug reservoir defined therein,wherein the device body comprises a hydrophobic elastomeric polyesterwhich degrades in vivo by surface erosion; and at least one drugformulation in the drug reservoir, wherein the device body providescontrolled release of the drug in vivo, wherein the implantable drugdelivery device is dimensioned and has an elasticity suitable fordeployment of the drug delivery device via urethral catheter ortransrectal injection into and retention in a seminal vesicle, prostate,ejaculatory duct, or vas deferens in a patient.
 36. The device of claim35, wherein the hydrophobic elastomeric polyester is apoly(glycerol-sebacic acid).
 37. The device of claim 35, wherein thedevice body comprises at least one aperture and provides controlledrelease of the drug in vivo by osmotic pressure.
 38. An osmotic pumpdevice comprising: a housing made of a bioresorbable elastomer andhaving at least one aperture; and a drug contained in the housing,wherein the pump device is configured to dispense the drug in vivo,driven by osmotic pressure, through the at least one aperture.
 39. Theosmotic pump device of claim 38, wherein the bioresorbable elastomercomprises a poly(glycerol-sebacic acid).
 40. The osmotic pump device ofclaim 38, which is dimensioned and has an elasticity suitable fordeployment into and retention in a seminal vesicle, prostate,ejaculatory duct, or vas deferens in a patient.
 41. A method of makingan implantable drug delivery device comprising: providing a pre-polymerfor forming a biocompatible, resorbable elastomer; extruding or moldingthe pre-polymer into a device body having an elongated shape whichcomprises a first end, an opposed second end, at least one sidewallbetween the first and second ends and a hollow bore defined by the atleast one sidewall; polymerizing the pre-polymer to produce across-linked elastomeric polymer; loading a drug formulation into thehollow bore; and closing off the hollow bore at positions to contain thedrug formulation therein to form an implantable drug delivery device,which is dimensioned and has an elasticity suitable for deployment ofthe drug delivery device via urethral catheterization or transrectalinjection into and retention in a genitourinary site in a patient.